Variant classification summary

NM_006231.4:c.2299G>A

POLE · NP_006222.2:p.(Glu767Lys) · NM_006231.4

GRCh37: chr12:133244109 C>T · GRCh38: chr12:132667523 C>T

Gene: POLE Transcript: NM_006231.4

Final call

VUS

PM2 supporting

Variant details

Gene

POLE

Transcript

NM_006231.4

Protein

NP_006222.2:p.(Glu767Lys)

gnomAD AF

6.815027755749406e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 Supporting reflects an extremely rare gnomAD v4.1 allele frequency of 6.81503e-06.

2

VUS: PM2 Supporting alone satisfies neither a pathogenic nor a benign classification combination.

Final determination: Under the custom POLE framework's ACMG/AMP combination rules, PM2 Supporting alone satisfies no pathogenic or benign rule, so the final call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.2299G>A is a missense substitution producing p.(Glu767Lys), not a named null-variant consequence eligible for PVS1.	pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	Not assessed: no previously established pathogenic variant producing the same p.Glu767Lys amino-acid change was documented in the reviewed evidence.
PS2	Not assessed	Not assessed: confirmed maternity, paternity, disease phenotype, and absence of family history are not documented for this variant.
PS3	Not assessed	Not assessed: No variant-specific functional assay was identified, and OncoKB reported no variant-specific reviewed functional evidence for POLE p.Glu767Lys.	oncokb PMID:25394175
PS4	Not met	Not met: the POLE-specific PS4 rule limits support to four listed recurrent hotspots, and c.2299G>A/p.E767K is not among them.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM1	Not met	Not met: p.E767K is absent from all 15 exact POLE substitutions authorized by the governing PM1 framework.	vcep_path_250_323 vcep_path_250_323_s002 vcep_path_250_323_s001
PM2	Met	Met at Supporting: gnomAD v4.1 AF is 6.81503e-06, below the <=0.0001 PM2 Supporting threshold, with 0 homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring testing establishes a pathogenic variant in trans.	clinvar
PM4	N/A	Not applicable: p.(Glu767Lys) is a missense substitution with no in-frame insertion, deletion, stop-loss, or protein-length change.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: no established pathogenic alternate missense variant at POLE residue 767 was documented in the reviewed evidence.
PM6	Not assessed	Not assessed: neither de novo status nor parental testing is documented for NM_006231.4:c.2299G>A.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or genotype–phenotype segregation data are documented.
PP2	Not assessed	Not assessed: the reviewed evidence does not establish both a low benign-missense rate and a common germline missense disease mechanism for POLE.
PP3	Not met	Not met: REVEL 0.352 lies in the generic missense gray zone [0.250, 0.750], and no governing POLE supplementary-table row was found.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype or family-history information is available to determine whether it is highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar has two Uncertain significance laboratory submissions and zero expert-panel submissions for this exact variant.	clinvar PMID:25394175
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 3.59e-06, far below the >=0.05 stand-alone BA1 threshold.	gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 3.59e-06, below the generic BS1 frequency threshold of 0.01.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes but does not document a qualifying healthy adult or the required inheritance and penetrance context.	gnomad_v4
BS3	Not assessed	Not assessed: No variant-specific functional assay demonstrated preserved POLE function or splicing; OncoKB reported no variant-specific reviewed functional evidence.	oncokb PMID:25394175
BS4	Not assessed	Not assessed: no affected-relative genotypes or phenotype data establish lack of segregation for this variant.
BP1	Not assessed	Not assessed: the reviewed evidence does not establish that POLE disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no pathogenic partner variant or phase information establishes either trans configuration or cis configuration.	clinvar
BP3	N/A	Not applicable: p.(Glu767Lys) is a missense substitution, not an in-frame deletion or insertion in a repetitive region.	pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.352 is above the generic BP4 cutoff of <0.250, and no governing POLE supplementary-table row was found.	vcep_path_250_323_s003 vcep_path_250_323_s004 revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular basis for disease is documented in the available case evidence.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely benign classification is present; both laboratory submissions are Uncertain significance.	clinvar PMID:25394175
BP7	N/A	Not applicable: c.2299G>A is missense and changes p.Glu767 to Lys, whereas BP7 is restricted to synonymous variants.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.